6-149400392-A-G

Position:

• chr6-149400392-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 8P and 6B. PVS1 BP6_Moderate BS2

The NM_001002255.2(SUMO4):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000694 in 1,613,946 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (7 hom.)
• Consequence: SUMO4 NM_001002255.2 start_lost
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.68

Genes affected

SUMO4 (HGNC:21181): (small ubiquitin like modifier 4) This gene is a member of the SUMO gene family. This family of genes encode small ubiquitin-related modifiers that are attached to proteins and control the target proteins' subcellular localization, stability, or activity. The protein described in this record is located in the cytoplasm and specifically modifies IKBA, leading to negative regulation of NF-kappa-B-dependent transcription of the IL12B gene. A specific polymorphism in this SUMO gene, which leads to the M55V substitution, has been associated with type I diabetes. The RefSeq contains this polymorphism. [provided by RefSeq, Jul 2008]

TAB2 (HGNC:17075): (TGF-beta activated kinase 1 (MAP3K7) binding protein 2) The protein encoded by this gene is an activator of MAP3K7/TAK1, which is required for for the IL-1 induced activation of nuclear factor kappaB and MAPK8/JNK. This protein forms a kinase complex with TRAF6, MAP3K7 and TAB1, and it thus serves as an adaptor that links MAP3K7 and TRAF6. This protein, along with TAB1 and MAP3K7, also participates in the signal transduction induced by TNFSF11/RANKl through the activation of the receptor activator of NF-kappaB (TNFRSF11A/RANK), which may regulate the development and function of osteoclasts. Studies of the related mouse protein indicate that it functions to protect against liver damage caused by chemical stressors. Mutations in this gene cause congenital heart defects, multiple types, 2 (CHTD2). Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

TAB2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• BP6: Variant 6-149400392-A-G is Benign according to our data. Variant chr6-149400392-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1700889.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUMO4	NM_001002255.2	c.1A>G	p.Met1?	start_lost	1/1	ENST00000326669.6	NP_001002255.1
TAB2	NM_001292034.3	c.1939+1208A>G		intron_variant		ENST00000637181.2	NP_001278963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUMO4	ENST00000326669.6	c.1A>G	p.Met1?	start_lost	1/1	6	NM_001002255.2	ENSP00000318635.4
TAB2	ENST00000637181.2	c.1939+1208A>G		intron_variant		1	NM_001292034.3	ENSP00000490618.1

Frequencies

GnomAD3 genomes AF: 0.00340 AC: 518 AN: 152260 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00111 AC: 278 AN: 249898 Hom.: 6 AF XY: 0.000887 AC XY: 120 AN XY: 135254

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.000399

Gnomad EAS exome AF: 0.000707

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000413 AC: 603 AN: 1461568 Hom.: 7 Cov.: 29 AF XY: 0.000377 AC XY: 274 AN XY: 727086

Gnomad4 AFR exome AF: 0.0114

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000576

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00339 AC: 517 AN: 152378 Hom.: 6 Cov.: 33 AF XY: 0.00325 AC XY: 242 AN XY: 74522

Gnomad4 AFR AF: 0.0115

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000473 Hom.: 0

Bravo AF: 0.00417

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00135 AC: 164

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 15, 2022

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.4
DANN	Benign	0.52
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.39	N
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.093
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.026	D
Vest4		0.71
MVP		0.29
ClinPred		0.015	T
GERP RS		0.23
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs78701690; hg19: chr6-149721528; COSMIC: COSV99644713;